Identification of Z-Tyr-Ala-CHN2, a cathepsin L inhibitor with broad-spectrum cell-specific activity against coronaviruses, including SARS-CoV-2

  • The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is partly under control by vaccination. However, highly potent and safe antiviral drugs for SARS-CoV-2 are still needed to avoid development of severe COVID-19. We report the discovery of a small molecule, Z-Tyr-Ala-CHN2, which was identified in a cell-based antiviral screen. The molecule exerts sub-micromolar antiviral activity against SARS-CoV-2, SARS-CoV-1, and human coronavirus 229E. Time-of-addition studies reveal that Z-Tyr-Ala-CHN2 acts at the early phase of the infection cycle, which is in line with the observation that the molecule inhibits cathepsin L. This results in antiviral activity against SARS-CoV-2 in VeroE6, A549-hACE2, and HeLa-hACE2 cells, but not in Caco-2 cells or primary human nasal epithelial cells since the latter two cell types also permit entry via transmembrane protease serine subtype 2 (TMPRSS2). Given their cell-specific activity, cathepsin L inhibitors still need to prove their value in the clinic; nevertheless, the activity profile of Z-Tyr-Ala-CHN2 makes it an interesting tool compound for studying the biology of coronavirus entry and replication.

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Author:Jordi DoijenORCiD, Koen TemmermanGND, Christel van der Eynde, Annick Diels, Nick van der BroeckORCiD, Michiel van Gool, Inha Heo, Steffen JaenschORCiDGND, Marleen Zwaagstra, Mayra Diosa ToroORCiD, Winston ChiuORCiD, Steven De JongheORCiD, Pieter LeyssenORCiD, Denisa BojkovaORCiDGND, Sandra CiesekORCiDGND, Jindrich CinatlORCiDGND, Lore Verschueren, Christophe BuyckORCiD, Franciscus Johannes Maria van KuppeveldORCiDGND, Johan NeytsORCiD, Marnix van LoockORCiD, Ellen van DammeORCiD
Parent Title (English):Microorganisms
Place of publication:Basel
Document Type:Article
Date of Publication (online):2023/03/10
Date of first Publication:2023/03/10
Publishing Institution:Universit├Ątsbibliothek Johann Christian Senckenberg
Release Date:2023/11/14
Tag:SARS-CoV-2; cathepsin L inhibitor; coronavirus; in vitro; phenotypic screening;
Issue:3, art. 717
Article Number:717
Page Number:20
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International